Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?

Annu Rev Immunol. 2001:19:163-96. doi: 10.1146/annurev.immunol.19.1.163.

Abstract

Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody Specificity
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / therapy*
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / therapy*
  • Chemotaxis, Leukocyte
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Combined Modality Therapy
  • Cytokines / physiology
  • Disease Models, Animal
  • Double-Blind Method
  • Etanercept
  • Humans
  • Immunization, Passive
  • Immunoglobulin G / immunology
  • Immunoglobulin G / therapeutic use
  • Immunoglobulin Heavy Chains*
  • Immunoglobulin gamma-Chains
  • Immunosuppressive Agents / therapeutic use
  • Infliximab
  • Mice
  • Multicenter Studies as Topic
  • Randomized Controlled Trials as Topic
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / therapeutic use
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / therapeutic use
  • Safety
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin gamma-Chains
  • Immunosuppressive Agents
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • CDP 571
  • Ro 45-2081
  • Infliximab
  • Etanercept